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Howe played junior hockey for the Detroit Jr. Red Wings. As a 15 year old, he led his Red Wings to the US Junior Championship in 1971. In 1972, the United States earned a Silver Medal at the 1972 Olympics in Sapporo, Japan with 16 year old Mark Howe as one of the stars. Howe eventually ended his junior hockey career playing for the Toronto Marlboros of the OHL, winning a Memorial Cup MVP in the process.

In 1973, he decided to play in the WHA alongside his brother, Marty and his father Gordie. Led by the Howes, the Houston Aeros won the 1974 and 1975 Avco Cups, awarded to the league champions of the WHA. Mark, playing left wing, was awarded the Lou Kaplan Award as Rookie of the Year and earned 2nd team All-Star status. He also represented his father's country in the 1974 Summit Series, where he was one of Team Canada's leading scorers.

When the NHL and WHA merged in 1979, one of the four WHA teams left standing were the Whalers. They changed their name to the Hartford Whalers and Mark Howe, his father and his brother continued one more season together, this time in the National Hockey League. The 1980–81 season proved to be one of Howe's best. Howe was a mid-season All-Star, and in the fall, he appeared for the US national team at the 1981 Canada Cup tournament.

Howe was involved in one of the more memorable injuries in NHL history. He slid into the pointed metal center of the net and cut a five inch gash in his upper thigh. He was essentially impaled by the metal, and the injury, which nearly ended his career, prompted the NHL to change the design of its nets so that there would no longer be a center portion that jutted up toward the goal line. He lost 35 pounds and his stamina suffered after requiring liquid diet to avoid intenstinal infections. Howe became damaged goods in the eyes of the Whalers management, so they moved Howe, in a 4 player deal that also involved draft picks, to Philadelphia.

Howe had his best season during the 1985–86 season where he posted some of the best numbers ever by an NHL defenseman. He scored 24 goals, added 58 assists for 82 total points. He led the NHL with a remarkable +85. He also added 7 shorthanded goals while being the lifeline out of the Flyers defensive zone with his outstanding skating & passing ability. Unfortunately for Howe, Edmonton's Paul Coffey had perhaps one of the best seasons by a defenseman in NHL history, breaking Bobby Orr's single-season records for goals and tallying 138 points. Howe, for the second time, finished 2nd in Norris Trophy voting.

The 1986–87 season brought great success to both Howe and his Philadelphia Flyers teammates. The Flyers, for the 3rd consecutive season, led the Prince of Wales Conference in points. Led by Howe, rookie netminder Ron Hextall, and a line featuring Brian Propp, Rick Tocchet and Pelle Eklund, the injury-riddled Flyers took the vaunted Edmonton Oilers to 7 games in the NHL Finals before succumbing 3-1 in the finale.

Howe, having struggled with both knee & back injuries, became a part-time player virtually the rest of his career. The decline in his games played coincided with the Flyers decline in play overall. It was no mystery to anyone watching the Flyers on a regular basis from the years 1988–91 why the team struggled. When Howe was in the lineup, the Flyers looked like a playoff team. Without him, they looked disorganized in their own end.

After the 1991–92 season, the Flyers granted Howe free agency so he could win the as-of-yet elusive Stanley Cup. He signed with the Detroit Red Wings, the team with which his dad had starred. The signing was a popular one in Detroit, as Mark was "returning home" to help build the Wings into a consistent playoff contender. He became a steadying influence on Detroit's young corps of defensemen, mostly notably Nicklas Lidström. He would have one more appearance in the Stanley Cup finals, but his Red Wings were swept in 1995 by the New Jersey Devils.

Mark Howe retired following the 1994–95 season, and assumed a scouting job with Red Wings, earning Stanley Cup rings when his teams captured championships in 1997, 1998, 2002, and 2008. Upon his retirement, Howe was the last active member of Canada's 1974 Summit Series team in the NHL.

Mark Howe was elected to Philadelphia Flyers Hall of Fame in 2001 and the United States Hockey Hall of Fame in 2003. As of 2008, he has not yet been inducted in the Hockey Hall of Fame. Currently, Howe serves in the Red Wings front office as Chief Pro scout. He makes his offseason home in the Philadelphia suburbs. Mark's son, Travis Howe, now works in hockey scouting and coaching.